1. Field of the Invention
The present invention concerns antitumor compounds. More particularly, the invention provides novel taxane derivatives, pharmaceutical compositions thereof, and their use as antitumor agents.
2. Background Art
Taxol.RTM. (paclitaxel) is a natural product extracted from the bark of Pacific yew trees, Taxus brevifolia. It has been shown to have excellent antitumor activity in in vivo animal models, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis. It has been recently approved for the treatment of ovarian cancer; and studies involving breast, colon, and lung cancers have shown promising results. The results of paclitaxel clinical studies are reviewed by Rowinsky and Donehower in "The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics" Pharmac. Ther., 52:35-84, 1991; and by K. C. Nicolaou et al. in "Chemistry and Biology of Taxol" Angew. Chem., Int. Ed. Engl., 33:15-44, 1994, and also in the references cited therein.
Recently, a semi-synthetic analog of paclitaxel named Taxotere.RTM. has also been found to have good antitumor activity in animal models. Taxotere.RTM. is also currently undergoing clinical trials in Europe and the United States. The structures of paclitaxel and Taxotere.RTM. are shown below along with the conventional numbering system of taxane molecules; such numbering system is also employed in this application. ##STR1##
One drawback of paclitaxel is its very limited water solubility. Accordingly, a number of research teams have prepared water-soluble derivatives, and some of them are disclosed in:
(a) Haugwitz et al., U.S. Pat. No. 4,942,184; Deutch et al., J. Medicinal Chemistry, 1989, 32, pp 788-792; PA1 (b) Kingston et al., U.S. Pat. No. 5,059,699; PA1 (c) Stella et al., U.S. Pat. No. 4,960,790; A. E. Mathew et al., J. Medicinal Chemistry, 1992, 35, pp 145-451; PA1 (d) European Patent Application 558,959 published Sep. 8, 1993; PA1 (e) European Patent Application 569,281 published Nov. 10, 1993; and PA1 (f) European Patent Application 604,910 published Jul. 7, 1994.